Throughout this application various publications are referred to in parentheses. Full citations for these references may be found at the end of each section of Experimental Details. The disclosures of these publications are hereby incorporated by reference in their entireties into the subject application to more fully describe the art to which the subject application pertains.
Group-wise analyses of imaging have demonstrated evidence of injuries or pathologies associated with adverse clinical outcomes. Although the injury or pathology is likely to have a unique spatial pattern in each patient, group analyses implicitly assume that location of injury will be the same across patients.
Diffusion Tensor Imaging (DTI), for example, reveals white matter abnormalities in mild traumatic brain injury (mTBI), consistent with traumatic axonal injury (TAI), the presumptive pathologic substrate of adverse clinical outcomes after TBI (e.g., 1-9). Analyses comparing groups of mTBI patients and controls, employed almost universally in mTBI research, implicitly assume location of injury will be the same across subjects. This approach is inherently insensitive to intersubject variation in location of pathology, a highly questionable assumption, given the wide variation in mechanism of injury and patient characteristics (10, 11). Furthermore, clinical use of DTI requires assessment of individual patients. An approach to identifying loci of brain injury in individual mTBI patients is needed to fully understand the nature and extent of mTBI pathology toward personalizing and improving clinical practice.
Few studies have assessed DTI in individuals (4, 8, 12, 13). Viviani, et al. used cross-validation, a resampling technique, to estimate the distribution of extreme values across the whole brain in stroke and glioblastoma (12). They proposed empirical and calibrated thresholds, based on the Family-Wise Error Rate (FWER). FWER for control of Type-I error rate in neuroimaging data may be overly conservative, however (14). Singh, et al. employed a “one vs. many” T-test, comparing TBI patients to a control group, utilizing a priori thresholds (individual voxel and cluster level), but not reporting validation or effectiveness testing of the thresholds (8). The “one vs. many” T-test approach has also been applied to chronic mTBI (4). Importantly, none of the published studies included validation to address efficacy or clinical utility of DTI as a diagnostic test.
At present, no method is available that allows quantitative detection of imaging abnormalities on a voxelwise basis in individual patients. The imaging methods themselves exist and are approved for human use, but are not utilized because no methods exist to extract meaningful information from the images. The ready availability of such an approach would open the door to quantitative imaging in clinical use. The present invention addresses the need for a personalized approach for detecting pathology or injury in individual patients, which could detect inter-individual differences and be applied in the clinical setting, where patients must be assessed as individuals.